Synthesis from amidoximes

Since the key thermal rearrangement was optimized, we turned our attention to earlier steps. The synthesis of amidoxime 7 was optimized from acetone cyanohydrin 4 (Scheme 6.6). The original Strecker reaction was carried out with ammonia... 

As detailed in CHEC-II(1996) <1996CHEG-II(4)179>, 4,5-dihydro-l,2,4-oxadiazol-5-ones are readily hydrolyzed, and further examples (see Equation 17) of this transformation have been reported involving the synthesis of amidoximes 126 from the dihydro-1,2,4-oxadiazol-5-one 115 <2004T10907>. 

Synthesis of some pyrazole derivatives from amidoximes was reviewed by Karbonits and Horvath. It has been shown that acrylophenone or methacrylophenone oximes (110) on treatment with BuONO in the presence of pyridine and copper(II) sulfate, and with subsequent interaction with dilute NaOH and acidification, gives 3(5)-phenyl-1-hydroxypyrazole 2-oxide or 4-methyl-3(5)-phenyl-l-hydroxypyrazole 2-oxide (111), respectively (equation 47) ... 

A general method for the synthesis of pyrimidine A-oxides from amidoximes is described. The conversion involves treatment of various carboxamide oximes 325 with 1,1,3,3-tetramethoxypropane, 2,4-pentanedione or 3-ethoxy-2-methylpropenal in the presence of CF3COOH to afford pyrimidine 1-oxides 326 (equation 141) . 

Thiemann s classical synthesis of 1,2,4-thiadiazoles3 from amidoximes continues to be used occasionally for preparative purposes. 1,2,4-Thiadia-zoles of type 137, for example, arise from ethyl cyanoglyoxalate arylhydra-zones (136) by the successive action of hydroxylamine and isothiocyanate esters.109 The heteryl-substituted 1,2,4-thiadiazole 138 has been obtained similarly.110... 

A reaction that is formally comparable to Thiemann s synthesis of 5-mercapto-1,2,4-thiadiazoles (141) from amidoximes (143) is the condensation... 

Oxadiazoles can be prepared by acylation of amidoximes. A variation of this method gives a one-pot synthesis from the amidoxime, an organic acid and a peptide coupling agent the method is sufficiently mild that there is no racemisation when mandelic acid is used. 1,2,4-Oxadiazoles can also be prepared from amides via acylamidines, " or via the cycloaddition of nitrile oxides to nitriles, as illustrated, or to 6>-methyl oximes. ... 

Scheme 12 Synthesis of 1,2,4-oxadiazoles from carboxylic acids and amidoximes using PS-reagents...

A synthesis of 5-unsubstituted 3-aryl-1,2,4-oxadiazoles starts from easily accessible A-(dicyano-vinyl)amidoximes (Schemes 61, 62) <86JAN111,94H(38)113>. 

In contrast with the classical synthesis, this reaction occurs in one step, in the absence of a solvent and the formed oxadiazole is easily isolated from the other reaction products. Even in the case of non- or mono-substituted oxadiazoles, the new reaction affords comparable or improved 3delds. The process is quite general. It concerns all kinds of amides and amidoxime salts and is generally carried out at the melting point of the mixture (100—200° C). 

Some new methods for the synthesis of the oxadiazole ring have been recently published. 1,2,4-Oxadiazoles can be easily obtained in a one-pot solvent-free process starting from P-keto esters 169 and amidoximes 170. The process is likely to go through an acyl ketene intermediate <07TL2231>. 

In related work, rapid synthesis of 1,2,4-oxadiazoles was achieved on polymer-supported reagents [109]. Two independent pathways were used to prepare these heterocycles from carboxylic acids and amidoximes under the action of microwave irradiation. In accordance with the conventional method using HBTU and N,N-diisopropylethylamine (DIEA) for synthesis of this heterocycle, a method utilizing polymer-supported bases was employed. The use of PS-BEMP in the presence of HBTU proved to be beneficial in the microwave procedure. Heating for 15 min in acetonitrile at 160 °C furnished high yields for a series of substrates. 1,2,4-Oxadiazoles can also be synthesized from carboxylic acid chlorides. Because these... 

Pyranosyl l-oxa-2,4-diazin-6(5//)-ones such as 131 have been isolated from reaction of the corresponding pyranosyl nitrile oxides with amino acid ethyl esters. Also, 131 has been proposed as an intermediate formed en route from the pyranosyl nitrile oxide to glycopeptide analogs. Once formed, 131 reacts with glycine ethyl ester at the C-6 carbonyl group to afford the ring-opened amidoxime 132 (Equation 20) <2004TL8913>. The synthesis of the precursor 131 is considered in Section 9.05.9.1.1. 

Oxadiazoles and 1,2,4-oxadiazoles are heterocyclic aromatic compounds that appear in many bioactive molecules. Previous methods for the synthesis of 1,2,4-oxadiazoles include the coupling of amidoximes with carboxylic acid derivatives, aerobic C—H oxygenation of amidoximes, or a cyclization of nitrile oxides to nitriles. Telvekar and Takale developed the preparation of 1,2,4-oxadiazoles from substituted diketone derivatives through a Beckmann rearrangement process tScheme S.3S1. When treated with diphosphorus tetraiodide in dichloromethane at room temperature, dioximes 150 formed the Beckmann products, 1,2,4-oxadiazoles 151, in excellent yields. 

Young and DeVita developed a novel procedure for the synthesis of oxadiaz-oles (Scheme 2.38a) [271]. Various oxadiazoles were prepared in moderate yields from aryl iodides and amidoximes under 1 bar of CO in a one-pot manner. Both electron-withdrawing and electron-donating substituents were tolerated. 

Cosford and coworkers presented a simple microreador setup for enabling multi-step synthesis of bis-substituted 1,2,4-oxadiazoles that required differential and controlled thermal treatments (between 0 and 200 °C) (Scheme 5.24) [34]. A base-assisted reaction between arylnitrile and hydroxylamine hydrochloride at 150°C in the first reactor produced amidoxime, which was quickly cooled to 0 °C before it was mixed with the add chloride. This mixture was then warmed and maintained at room temperature for 2 min in the connected tube before it entered a superheated chip-microreador where the high temperature (200 °C) and pressure (7.5-9.0 bar) accelerated the reaction leading to 40-63% of differently functionalized oxadiazoles within 30 min of total process time. Relativdy inferior yields were obtained from over three-day-long reaction in a sealed tube for the same products. 

The synthesis of fluorinated oxadiazoles can be achieved from open-chain flnorinated precursors through conventional heterocyclization reactions such as the amidoxime route (i in Scheme 1) and the cycloaddition route (ii in Schane 1), both necessitating of a nitrile precursor [7]. 

The treatment of alkyl borates, phenylboronic acid, and boric acid with amidoximes has resulted in the synthesis and characterization of twenty-seven 1,3,5,2-oxadiazaboroles. Dimeric amidoboranes which result in boron-nitrogen-oxygen heterocyclic systems as well as monomeric iminoboranes in equilibrium with monomeric amidoboranes are produced from the reaction of iVD-bis(trimethylsilyl)acylamides with halogenodiorganylboran. ... 

Some examples in which carbonylative and cychzation steps work separately in a one-pot procedure dealing with the synthesis of oxadiazoles 34 [43,44], quinolines, and naphthyridines 35 [45] have been reported. Oxadiazoles were prepared via palladium-catalyzed cyclocarbonylation of aryliodides or diaryliodonium salts with amidoximes (Scheme 13.16). The acylpalladium complex generated from oxidative addition-insertion reaction between aryliodide/iodonium salt, Pd(0), and carbon monoxide reacts with the amidoxime giving rise, after reductive elimination of Pd(0), to an O-acyl-amidoxime, which in turn undergoes cydodehydratation to oxadiazole in moderate to good yields. 

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